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Total Synthesis of Highly Oxygenated Icetexane Diterpenoids

高含氧Icetexane二萜的全合成

基本信息

批准号：
8200233
负责人：
Felipe de Jesus Cortez
金额：
$ 1.55万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2011-07-14
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The development of new strategies and methods for the total synthesis of biologically active natural products and medicinally important compounds are important for the study of general medicine. By building complex molecules, we gain access to significant quantities of natural products with biological activity for further testing. In addition, we gain the ability to access analogs of these compounds in an attempt to improve bioactivity. The focus of the research is the development and utilization of a new cycloisomerization reaction or the synthesis of seven-membered rings and its application to the total synthesis of a biologically important family of natural products. Specifically, this project focuses on A) the use of gallium salts, which are cheaper and less toxic than other commonly used cycloisomerization metal catalysts, to activate alkynes in the isomerization of indene intermediates to form seven-membered rings as well as, B) the utilization of this methodology in the total synthesis of natural products with biological activity. This methodology can be applied to the total synthesis of the icetexane natural products, isolated from various members belonging to the Salvia genus. The members of this family have been shown to exhibit interesting biological activities. For example, komaroviquinone, isolated from Dracocephalum komarovi, shows trypanocidal activity against the infectious form of Trypanosoma cruzi, the causative agent for Chagas' disease. Another important bioactivity displayed by komaroviquinone is inhibition of the chemokine receptor CCR5, which plays a vital role in HIV infection. Inhibition of CCR5 could lead to a general method for curbing infection. Icetexone, anastomosine, and dihydroanastomosine are three compounds in this family that have yet to be synthesized. They differ from other members in the family through the inclusion of an additional 5- membered lactone ring. The bioactivity of these compounds has not been fully studied; however, preliminary accounts suggest that the C5 epimer of icetexone displays trypanocidal activity comparable to that found in komaroviquinone. The study of methodology and total synthesis benefits public health by allowing for the synthesis of molecules that can lead to more effective treatments for common diseases, such as Chagas' disease. These studies can also lead to the synthesis of analogs of molecules that may improve on current treatments of disease.

描述(申请人提供)：开发全合成具有生物活性的天然产物和具有重要药用价值的化合物的新策略和新方法对普通医学的研究非常重要。通过构建复杂的分子，我们可以获得大量具有生物活性的天然产品进行进一步测试。此外，我们还获得了获取这些化合物的类似物的能力，以试图提高生物活性。研究的重点是开发和利用一种新的环异构化反应或七元环的合成，并将其应用于一类具有重要生物意义的天然产物的全合成。具体地说，该项目的重点是：A)使用镓盐，它比其他常用的环异构化金属催化剂更便宜，毒性更低，在吲哚中间体的异构化反应中激活炔烃形成七元环，以及B)在具有生物活性的天然产物的全合成中使用这一方法。该方法可用于从丹参属不同成员中分离出来的icetexane天然产物的全合成。这个家庭的成员已经被展示出有趣的生物活动。例如，从青青树中分离出的柯马罗维醌对克氏锥虫的感染形式具有杀锥虫活性，克氏锥虫是恰加斯病的病原体。另外一个重要的生物活性是抑制趋化因子受体CCR5，CCR5在HIV感染中起着至关重要的作用。抑制CCR5可能导致抑制感染的一般方法。依西酮、蛇床子素和二氢蛇床子素是该家族中的三个尚未合成的化合物。它们与家族中的其他成员不同，因为包含了一个额外的5元内酯环。这些化合物的生物活性还没有得到充分的研究；然而，初步的研究表明，icetexone的C5同分异构体显示出与Komaroviquone中发现的类似的杀锥虫活性。方法学和全合成的研究有利于公众健康，因为它允许合成分子，从而导致对查格斯病等常见疾病的更有效治疗。这些研究还可以导致合成分子的类似物，这些分子可能会改进目前的疾病治疗。